Abstract
Renal cell carcinoma (RCC) is the sixth most common cancer in the US. However, no significant changes in management have occurred since the tyrosine kinase era until the recent breakthrough with checkpoint inhibitors. Therefore, the need for more therapeutic options is paramount. Our objective was to determine whether PARP inhibition represents a novel therapeutic option for RCC. We used publicly available COSMIC, GDC Data Portal, and cBioPortal databases to explore mutations in DNA repair genes in RCC tissues from the TCGA cohort. We treated a human normal renal epithelial cell line RPTEC/TERT1 and two human renal cancer cell lines ACHN and CAKI-2 with PARPi niraparib, olaparib, rucaparib, veliparib, and talazoparib. Cell survival, cell proliferation, clonogenic ability, and apoptosis were assessed. RCC xenografts in SCID mice were treated with PARPi to evaluate their efficacy in vivo. Data mining revealed that ~27-32% of RCC tissues contain mutations in homologous recombination genes. Niraparib and talazoparib were the most effective at reducing cell survival, proliferation, and clonogenic ability in vitro. Niraparib, talazoparib, and rucaparib were the most effective in reducing RCC xenograft growth in vivo. Agents such as PARPi that exploit mutations in DNA damage repair genes may be effective therapeutic options for RCC.
Highlights
Renal cell carcinoma (RCC) is the ninth most prevalent cancer world-wide and in the US [1]
We aimed to test whether Poly (ADP) Ribose Polymerase (PARP) inhibition would be a viable therapeutic strategy for RCC using Clearcell RCC (ccRCC) and papillary RCC (pRCC) cell lines
Inhibitors of the mammalian target of Rapamycin (mTOR) pathway have been used in the management of mRCC
Summary
Renal cell carcinoma (RCC) is the ninth most prevalent cancer world-wide and in the US [1]. Most patients present with localized disease, and definitive local treatment remains the gold standard for patients with no distant metastases [3, 4], while systemic drug therapy is an established practice for metastatic disease [5,6,7]. The US Food and Drug Administration (FDA) has approved several systemic therapies including anti-angiogenic agents, mammalian target of Rapamycin (mTOR) inhibitors, and PARP Inhibition as a Therapeutic Strategy in RCC immunotherapeutic agents for the treatment of RCC [8]. While the overall survival of patients with metastatic RCC has improved with these systemic therapies, disease progression and mortality are inevitable in most patients with advanced RCC.
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